• A novel functional DNA G-quadruplex in SLC45A1 is identified, and its disruption by the c.449G>A variant leads to transcriptional enhancement and gain-of-function, contributing to intellectual developmental disorder with neuropsychiatric features.
• The study provides the first mechanistic link between DNA G4 structural alterations and SLC45A1 pathogenicity, highlighting the role of non-canonical DNA structures in neurodevelopmental disorders.
• The c.449G>A variant upregulates SLC45A1 mRNA and protein expression, suggesting a potential therapeutic target for modulating SLC45A1 levels in related conditions.
• The findings underscore the importance of DNA G4s in gene regulation and brain development, opening new avenues for investigating other genetic disorders associated with G4 disruptions.